DESCRIPTION: (Applicant's Abstract) Methamphetamine is a potent psychomotor stimulant drug with high potential for abuse, and recent surveys indicate that its popularity is increasing. In animals, methamphetamine is a documented dopamine (DA) and serotonin (5-HT) neurotoxin. In baboons, doses on the order of those abused by human have recently been found to damage brain DA and 5-HT neurons. The overall goal of the present studies is to determine whether humans with a history of methamphetamine abuse show evidence of brain DA or 5-HT neural injury. To achieve this goal, the specific aims of the project will be: (1) To use PET imaging with [11C] WIN-35,428 to determine if humans with a history of methamphetamine abuse show evidence of a lasting decrease in striatal DA transporter sites; 2) To use PET imaging with [11C]DTBZ to ascertain if humans with a history of methamphetamine exposure evidence of a lasting reduction in striatal VMAT2 sites; 3) To determine if humans with a history of extensive methamphetamine use are more sensitive to the effects of the catecholamine-depleting agent a-methyparatyrosine exposure show evidence of a lasting reduction in striatal VMAT2 sites; 3) To determine if humans with a history of extensive ethamphetamine use are more sensitive to the effects of the catecholamine-depleting agent a-methylparatyrosine (a-MPT) 4) To use PET imaging with the 5-HT transporter ligand [11C] McN5652 to determine if humans with a history of methamphetamine abuse show evidence of a lasting decrement in 5-HT transporter sites. By pursuing these specific aims, this research will test the hypothesis that prior exposure to repeated doses of methamphetamine produces a lasting reduction of brain DA and 5-HT axonal markers in humans. In these studies, abstinent methamphetamine abusers will be compared to individuals who have abused drugs other than methamphetamine and to control subjects without a history of drug abuse or dependence. In addition, a positive control group consisting of subjects with Parkinson's disease will be studied. The long-term goals of the project are to detect subclinical DA and 5-HT neural injury in abstinent methamphetamine users (if such injury occurs), and to better delineate the neurobiologic and public health consequences of abuse of methamphetamine and related drugs.